Dose-escalation Study of Oral Etoposide and Carboplatin in Patients with Advanced Lung Cancer

A dose-escalation study of daily etoposide and carboplatin wascarried out on 23 patients with advanced lung cancer using astarting dose of 40 mg/m²/day etoposide given orally for 21days and 250 mg/m² carboplatin given intravenously (IV) on day1. A total of 41 courses were given. Myelosuppression was themajor dose-limiting toxicity. The maximum tolerated dose wasreached at the fourth level with 40 mg/m²/day etoposide for21 days and 400 mg/m² carboplatin on day 1, once every 4 weeks.Non-hematological toxicities were generally mild or reversible.The recommended doses of this combination chemotherapy are 40mg/m²/day etoposide for 21 days and 350 mg/m² carboplatin onday 1. The response rate for non-small cell lung cancer andsmall cell lung cancer was 16.7% and 60% (95% confidence intervalsof 3.6% to 41.4%, and 14.7% to 94.7%), respectively. A phaseII study is necessary to define the efficacy and safety of thiscombination chemotherapy.     

Intensive Chemotherapy for Anaplastic Thyroid Carcinoma: Combination of Cisplatin, Doxorubicin, Etoposide and Peplomycin with Granulocyte Colonystimulating Factor Support

The Japanese Society of Thyroid Surgery undertook a pilot studyof treatment for anaplastic thyroid carcinoma in a cooperativesetting. The treatment consisted of cisplatin 40 mg/m² dripintravenous infusion (div), day 1, adriamycin 60 mg/m² iv, day1, etoposide 100 mg/m²/day div, days 1–3, peplomycin 5mg/body/day sc, days 1–5 and granulocyte colony-stimulatingfactor (GCSF) 2 µg/kg/day sc, days 6–14. This wasscheduled to be repeated every 3 weeks. Local radiation therapywas added for patients in whom it was indicated. A total of17 patients (mean age, 66 yr) were enrolled. Ten patients hadadvanced disease with measurable lesions and 2 patients experiencedpartial remission lasting 2 and 3 months, respectively. Sixof 7 patients were treated with the same modality of treatmentas an adjuvant. Three died of progressive disease after 3–7months and three others have survived for 3–11 months.The toxicities of the chemotherapy were mainly bonemarrow suppression,despite G-CSF support. Transient liver dysfunction was alsonoticed. These results indicate that this combined a treatmentcan be given to patients with acceptable toxicity. The degreeof leukopenia was greater than expected, partly due to the advancedage of the patients and the low dose of G-CSF. In addition,8 available thyroid specimens were examined for the mdr 1 geneand P-glycoprotein, but all were negative. Further study ofanaplastic thyroid carcinoma by this cooperative group willbe carried out.     

FAC (fluorouracil, doxorubicin, cyclophosphamide) as second line chemotherapy in patients with metastatic breast cancer progressing under FEC (fluorouracil, epirubicin, cyclophosphamide) chemotherapy

Background: The cross-over resistance between different anthracyclinesin breast carcinoma has not been largely evaluated in clinicaltrials. Patients and methods: Nineteen patients with metastatic breastcancer who had failed prior first line FEC chemotherapy (fluorouracil500 mg/m², epirubicin 50 mg/m² cyclophosphamide 500 mg/m², every4 weeks) were treated with a combination of fluorouracil 500mg/m², doxorubicin 50 mg/ m² and cyclophosphamide 500 mg/m²every 4 weeks (FAC). Results: Five patients achieved partial responses, ranging induration from 5 to 8 months. The main toxicity was cardiac,with congestive heart failure documented in five patients. Conclusion: The findings indicate an absence of cross-resistanceof doxorubicin in some epirubicin-resistant patients. breast cancer, anthracyclines, cross-resistance     

Effect of granulocyte colony-stimulating factor administration in elderly patients with aggressive non-Hodgkin's lymphoma treated with a pirarubicin-combination chemotherapy regimen

PURPOSE:: Results of a multidrug chemotherapy regimen consisting of cyclophosphamide,pirarubicin, teniposide, and prednisolone (CTVP) plus subcutaneousgranulocyte colonystimulating factor (G-CSF) in elderly patientswith aggressive non-Hodgkin's lymphoma (NHL) are reported. PATIENTS AND METHODS:: Between January and December 1992, 46 previously untreated patientsolder than 69 years with intermediate- and high-grade NHL receivedcyclophosphamide 750 mg/m², teniposide 75 mg/m², pirarubicin50 mg/m² day 1, and prednisolone 40 mg/m² days 1 to 3. G-CSF,5 µg/kg/day, was administered from day 4 up to day 14or when the absolute neutrophil count reached 5 x 10⁹/1. Sixcycles were scheduled every 3 weeks. RESULTS:: Grade 3 or grade 4 neutropenia complicated 22% and 26% of chemotherapycycles, respectively. Fever or/and clinical infection were observedin 4% and 14% of cycles. One toxic death related to a septicshock occurred. Eight cycles (4%) were delayed with a medianduration of 7 days. Administered median dose intensity was 93.5%.Objective response rate was 74% and 46% of the patients achieveda complete response. The 2-year overall survival and eventfreesurvival rates were 47% and 28%. CONCLUSION:: In comparison with a previous group of patients treated withCTVP, G-CSF allows delivery of chemotherapy with a reduced neutropenia-inducedmorbidity in an outpatient setting in elderly patients withaggressive NHL without modifying response rate or survival. chemotherapy, elderly, G-CSF, lymphoma     

Phase II study of a closely spaced ifosfamide--cisplatin schedule with the addition of G-CSF in advanced non-small-cell lung cancer and malignant melanoma

BACKGROUND:: Ifosfamide and cisplatin are frequently combined cytotoxic agents.Both have a dose-response relationship. In view of this it appearsattractive to study regimens with a higher dose intensity thanusual. One way to increase the dose intensity is to shortenintervals between chemotherapy cycles. As bone marrow toxicityis dose limiting in ifosfamide-cisplatin combinations we starteda phase II study with both drugs administered every 2 weeksin combination with G-CSF. PATIENTS AND METHODS:: Patients with advanced non-small-cell lung cancer or malignantmelanoma were eligible for the study. The treatment consistedof ifosfamide 2 gram/m²/day days 1–3 combined with mesna,and cisplatin 33 mg/m²/day days 1–3, administered in hypertonicsaline (3% NaCl). G-CSF was started on day 4 at a dose of 5µg/kg/day and was continued until day 12. The cycles wereto be repeated every 2 weeks for a maximum of 6 cycles. RESULTS:: Thirty-two patients were entered in the study; 30 patients wereevaluable for response and toxicity. Neutropenia (grade 4 in16 patients) and thrombocytopenia (grade 4 in 15 patients) werethe most common toxicities. Thrombocytopenia incidence and -durationincreased per cycle and was the main cause of treatment delaysespecially after the third cycle. Only 4 patients were ableto complete the planned treatment without any delay or dosereduction and reached the intended dose intensity of 3 gram/m²/weekof ifosfamide and 50 mg/m²/week of cisplatin. Non haematologictoxicities were generally mild. Out of 22 evaluable patientswith non-small cell lung cancer 6 responded (27%; 95% CI: 10%–48%)while only one out of 8 patients with melanoma responded. Themedian response duration was 26 weeks (range 16–36 weeks). CONCLUSION:: The planned high-dose intensity of ifosfamide and cisplatincould be reached only for the first 2–3 cycles. Haematologictoxicity, especially cumulative thrombocytopenia, necessitatedtreatment delays jeopardizing the dose intensity. The responserate in non-small-cell lung cancer and melanoma was not superiorto what can be expected from more conventional regimens. cisplatin, G-CSF, ifosfamide, phase II study     

5-Fluorouracil, folinic acid, epidoxorubicin and cisplatin (FLEP) combination chemotherapy in advanced measurable gastric cancer. A phase II trial of the Spanish Cooperative Group for Gastrointestinal Tumor Therapy

BACKGROUND:: Metastatic disease is a common problem in gastric cancer andthe development of better chemotherapeutic regimens is a clearpriority in gastrointestinal oncology. PATIENTS AND METHODS:: Ninety consecutive, previously untreated patients with unresectableor measurable metastatic gastric cancer were included in a multicenterphase II trial with a combination of folinic acid (200 mg/m²)and 5-fluorouracil (400 mg/m²) days 1-3, with epidoxorubicin(60 mg/m²) and cisplatin (100 mg/m²) on day 2. RESULTS:: A total of 376 courses of FLEP were given, with a median offour courses per patient. Objective responses were observedin 32 (35%) patients (CI at 95%: 25.7%-46.3%). Eight (9%) patientsexperienced clinical complete remissions. Median time to progressionwas 25 weeks for the entire group of patients and 38 weeks forresponders. Myelo-suppression was the primary toxicity. WHOgrade 3 leuko-penia appeared in 26 patients (29%). Ten presentedepisodes of febrile neutropenia requiring hospitalization, butno toxic deaths were observed. Grades 3 and 4 thrombocytopeniawere seen in 8 and 1 patients, respectively. Median survivaltime was 8 months for all treated patients and 11 months forresponders. CONCLUSIONS:: The FLEP regimen is an active combination in advanced gastriccancer with moderate toxicity that warrants further testingin a phase III trial. advanced gastric cancer, combination chemotherapy, phase II trial     

Dose escalation of high-dose cyclophosphamide and etoposide with high-dose doxorubicin (CDE) and filgrastim for poor-risk non-Hodgkin's lymphoma

PURPOSE:: To identify the highest possible dose of cyclophosphamide (C)and etoposide (E) to be given with high-dose doxorubicin (D)and filgrastim (G-CSF) but without stem cell support in high-risknon-Hodgkin's lymphoma. PATIENTS AND METHODS:: High-dose CDE was given to 18 evaluable patients, 5 had previouschemotherapy. All patients received D 90 mg/sqm and G-CSF 20µg/kg/day. The first cohort had C 1800 mg/sqm and E 450mg/sqm. Chemotherapy was given in equally divided doses overthree days. Dose escalation was performed thrice up to C 3900mg/sqm and E 975 mg/sqm. One to four courses were given. RESULTS:: The median number of days (quartile values) with neutrophils<0.5 x 10⁹/l was 9 days (7–10), untransfused platelets<20 x 10⁹/l 6 days (3–7), fever     

A prospective randomized phase III study in non-small-cell lung cancer comparing cisplatin, ifosfamide, vinblastine (VIP) versus cisplatin, ifosfamide and etoposide (VIP-16)

BACKGROUND:: It was recently reported that when ifosfamide was added to cisplatinand vinblastine the response rate was increased but not thesurvival in patients with non-small-cell lung cancer (NSCLC).The purpose of this study was to investigate the possibilityof increased responses and survival with use of the combinationof cisplatin, ifosfamide, etoposide (VIP-16) in comparison tothecombination of cisplatin, ifosfamide, vinblastine (VIP) in non-operableNSCLC. PATIENTS AND METHODS:: Two hundred twelve patients with histologically confirmed diagnosesof NSCLC were randomized into two groups: group A received cisplatin100 mg/ m², vinblastine 6 mg/m² and ifosfamide 3 mg/m² i.v.on day 1 every 3 weeks; group B received the same regimen exceptthat etoposide 120 mg/m² was substituted for vinblastine ondays 1, 2, and 3. Patients were well balanced for age, sex,performance status (PS), stage, grade, histology and sites ofdisease, and the relative dose intensity was similar in bothgroups. RESULTS:: One hundred one patients were evaluable for response in groupA and 99 in group B. The overall response rates were 29% ingroup A (5CR) and 25% in group B (3CR). The median time to progressionwas 7.51 (2–35) months for group A and 7.7(1–28)months for group B (P=0.34). The median survival was 8.49 (0.33–37.44)months for group A and 9.38 (0.43–36.59) for group B (P=0.39).Multivariate Cox stepwise analysis showed stage to be the onlysignificant prognostic factor for survival (P=0.0114). Toxicitywas not remarkable and not different between the two groupsexcept for alopecia which was much more common in the patientswho received etoposide. CONCLUSION:: VIP and VIP-16 combination chemotherapies are equally activein NSCLC with acceptable toxicity. Stage proved to be the mostsignificant prognostic factor for survival in this study. chemotherapy, cisplatin, NSCLC, randomized     

Neoadjuvant Chemotherapy with Etoposide, Leucovorin, 5-Fluorouracil and Cisplatin for Advanced Esophageal Squamous Cell Carcinoma

Eighteen patients with invasive periadventitial tissue (T4)or distant lymph node metastatic (M1,LYM) squamous cell carcinomawere entered into a pilot study of neoadjuvant chemotherapywith etoposide (50 mg/m²/day, days 1–5), leucovorin (30mg/body/day, days 2–5), 5-fluorouracil (5-FU; 400 mg/m²/day,days 2–5) and cisplatin (100 mg/m²–day, day 1) (ELFP).The overall response rate was 56%. The response rates in theT4 tumor and M1, LYM patients were 56 and 50%, respectively.Radical esophagectomies were performed on six of 17 patientswho had completely recovered from the chemotherapy, a resectabilityof 35%. Histologically, the primary tumor was moderately toslightly effective, and the lymph nodes markedly to moderatelyeffective. Histologic responses in the lymph nodes were differentfrom those in the primary tumors and in each node. There werefour chemo-surgically related deaths. Median survival timesin responding and non-responding patients were nine and threemonths, respectively. In conclusion, neoadjuvant chemotherapywith ELFP appears to be effective against esophageal squamouscell cancer with periadventitial tissue invasion or distantlymph node metastasis. Chemo-surgically related deaths werehowever, 22%, showing neoadjuvant chemotherapy to necessitateextremely careful attention to the medical and surgical managementof patients.     

Etoposide and carboplatin as salvage and first-line therapy in ovarian cancer patients

Background: The agents etoposide and carboplatin are activeagainst ovarian cancer and display synergistic anti-tumor activityin animal tumor models. The objective of these two phase IItrials was to determine the efficacy and toxicity of the combinationof etoposide with carboplatin in previously treated and untreatedpatients with ovarian cancer. Patients and methods: Etoposide (100 mg/m²) was administeredas a one-hour infusion on three consecutive days and carboplatin(400 mg/m²) as a 30-minute infusion on day 2 of each monthlyscheduled cycle. In 20 patients, previously treated with cisplatin-containingregimens, a total of 102 cycles was applied as salvage therapy(ST) and in 27 patients, a total of 168 cycles as first-linetherapy (FLT). Results: ST yielded 2 complete remissions (CR) and one partialremission (PR); in 7 patients, no evidence of disease (NED)and in 6 patients, no change (NC) were observed. The progression-freeintervals (PFI) lasted a median 7.0 months (range ± 2–14months). FLT resulted in 7 CR (4 of them pathologically (p)verified), 11 NED (1 pNED), 3 PR (1 pPR) and 6 NC. The objectiveresponse rate was 63% (95% confidence interval: 36-89%). PFIlasted a median 8.0 months (range 3–25+ months); mediansurvival had not been reached at the time of evaluation. Thrombocytopenia(WHO grade 4) was the limiting toxicity. Conclusions: Although not fulfilling the expectations of synergisticactivity as shown in preclinical models, the combination ofetoposide with carboplatin is an active and feasible therapyregimen in the out-patient management of ovarian cancer. etoposide/carboplatin, first-line therapy, ovarian cancer, phase II study, salvage therapy     

Chemotherapy of invasive thymoma

Thirty-two patients with stage III or IV invasive thymoma (14 women and 18 men; median age, 40 years) were treated at the Padua Medical Oncology Department from 1977 to 1988. All patients received the following chemotherapy in 4-day courses: 50 mg/m2 of cisplatin intravenously (IV) and 40 mg/m2 of doxorubicin IV on day 1; 0.6 mg/m2 of vincristine IV on day 3; and 700 mg/m2 of cyclophosphamide IV on day 4 (ADOC). The courses were repeated every 3 weeks, and toxic effects were tolerable. The radiologically defined overall clinical response rate (complete plus partial response) was 91% with 47% clinical complete remissions; median time to progression was 11 months (range, 0 to 96) and the median estimated (Kaplan-Meier) progression-free interval was 22 months. Five of the 15 clinical complete remissions were pathologically confirmed at thoracotomy. We believe the ADOC regimen qualifies for adjuvant and preoperative treatment of invasive thymoma due to the high complete response and overall response rates.     

Phase I Study of a Weekly Infusion of Irinotecan Hydrochloride (CPT-11) and a 14-day Continuous Infusion of Etoposide in Patients with Lung Cancer: Japan Clinical Oncology Group 9408

Background: To determine the maximum-tolerated dose (MTD) andacceptable dose level of CPT-11 in combination with a 14-daycontinuous infusion of etoposide in patients with refractoryadvanced lung cancer (LC), especially small cell lung cancer(SCLC). Methods: Etoposide was administered continuously at 25 mg/m²/dayfor 14 days. The initial dose of CPT-11 was 40 mg/m² given asa 90-min intravenous infusion on days 1, 8 and 15 and the doseescalation of CPT-11 was planned in increments of 20 mg/m² untilsevere or life-threatening toxic effects were observed. Results: Eight refractory advanced LC patients entered thisstudy, of whom two were not assessable for toxicity becauseof patient’s refusal and progressive disease. One treatment-relateddeath due to pulmonary toxicity and one patient with hypotensionwho needed catechol­amine for more than 48 h were observedat a CPT-11 dose of 40 mg/m². The MTD of CPT-11 was 40 mg/m².Therapeutic efficacy could be assessed in six patients, of whomtwo achieved a partial response. Conclusions: This regimen was too toxic and the recommendeddose was outside this study. One has to consider pulmonary toxicitywhen using CPT-11, especially for patients previously treatedwith cytotoxic agents for which pulmonary toxicity has beenreported. ⁺ For reprints and all correspondence: Tetsu Shinkai, Divisionof Medical Oncology, National Cancer Center Hospital, 1–1,Tsukiji 5-chome, Chuo-ku, Tokyo, Japan. E-mail: tshinkai@ncc.go.jpAbbreviations:JCOG, Japan Clinical Oncology Group; CPT-11, irinotecan hydrochloride;MTD, maximum tolerated dose; LC, lung cancer; SCLC, small celllung cancer; LD, limited disease; ED, extensive disease; NSCLC,non-small cell lung cancer; ECOG, Eastern Cooperative OncologyGroup; PS, performance status; WBC, white blood cell; Hb, hemoglobin;CBC, complete blood cell; ECG, electrocardiogram; CT, computerizedtomography; DLT, dose-limiting toxicity; WHO, World Health Organization;TRT, treatment-related death; GOT, glutamic–oxaloacetictransaminase; GPT, glutamic–pyruvic transaminase; LDH,lactate dehydrogenase; ALP, alkaline phosphatase; BUN, bloodurea nitrogen; G-CSF, granulocyte colony-stimulating factor;MMC, mitomycin C; MVP, combination therapy of mitomycin C, vindesineand cisplatin; CODE, combination therapy of cisplatin, vincristine,doxorubicin and etoposide; PR, partial response; SD, stabledisease; PD, progressive disease; NE, not evaluable     

Patient with Extensive Small Cell Lung Cancer Given Moderately Doseintensified Chemotherapy and Peripheral Blood Stem Cell Support

Although recent progress in multi-drug chemotherapy has increasedthe median survival of patients with extensive Small cell lungcancer (SCLC) to 7 months, 2-year survivors are still exceptional.We describe a 40-year-old man with extensive SCLC involvingthe lungs and systemic nodes who was initially treated with6 cycles of an alternating combination regimen consisting ofcyclophosphamide, doxorubicin, vincristine, cisplatin and etoposide.After the second cycle of the regimen, Peripheral blood stemcells (PBSC were harvested and frozen. The patient then receiveda moderately dose-intensified regimen consisting of cisplatin(80 mg/m²)and etoposide (500 mg/m²x3), followed by infusionof the thawed PBSC. Hematopoietic recovery was rapid, and thepatient remained tumor-free for 12 months until multiple tumorrecurrence.     

Dose-intense therapy with etoposide, ifosfamide, cisplatin, and epirubicin (VIP-E) in 100 consecutive patients with limited- and extensive-disease small-cell lung cancer

Background: We conducted a phase I/II trial to assess the feasibilityand activity of VIP-E chemotherapy in small-cell lung cancer. End-points weretreatment-related morbidity and mortality, response to treatment, duration ofresponse, and survival.Patients and methods: Two cycles of combination chemotherapy followedby granulocyte colony-stimulating factor (G-CSF) were given at a dose ofetoposide (500 mg/m²), ifosfamide (4000mg/m²), cisplatin (50 mg/m²), and epirubicin(50 mg/m²) to 100 consecutive patients with SCLC. Thirtypatients (19 with LD, and 11 with ED SCLC) proceeded to VIC-E high-dosechemotherapy with autologous peripheral blood stem cell transplantation(PBSCT) at a cumulative dose of etoposide 1500 mg/m²,ifosfamide 12,000 mg/m², carboplatin 750 mg/m²and epirubicin 150 mg/m² (VIC-E). Surgical resection ofprimary tumor was attempted at the earliest feasible point. Thoracicirradiation was given after completion of chemotherapy.Results of conventional-dose VIP-E: 97 patients were evaluable forresponse. Objective response rate was 81% in LD-SCLC (33% CR,48% PR; excluding patients in surgical CR) and 77% in ED-SCLC(18% CR, 58% PR). Treatment mortality was 2%. Mediansurvival was 19 months in LD-SCLC and 6 months in ED-SCLC. Two-year survivalwas 36% in LD and 0% in ED SCLC.Results of high-dose VIC-E: All 30 patients improved on or maintainedprior responses. Four patients (13%) died of treatment-relatedcomplications. Median survival was 26 months in LD-SCLC and 8 months inED-SCLC. Two-year survival was 53% in LD and 9% in ED SCLC.Conclusion: VIP-E chemotherapy is an effective induction therapy forSCLC. Compared with traditional protocols such as ACO orcarboplatin/etoposide, response rates are slightly improved, while survivalis not different. In the LD SCLC subgroup, high-dose chemotherapy improvedresponse rates and survival, especially for patients in surgical CR prior tohigh-dose therapy. In ED SCLC, however, higher response-rates did nottranslate into improved survival. Selected LD-SCLC patients with good partialor complete remissions after prior therapy may benefit from HDC and PBSCT.     

Phase III randomized trial of dose intensive neoadjuvant chemotherapy with or without G-CSF in locally advanced breast cancer: long-term results

Objective.

To compare the pathologic complete response (pCR) rate of patients treated with 5-fluorouracil (5-FU), doxorubicin, and cyclophosphamide (FAC) versus dose-intense FAC plus G-CSF in the neoadjuvant setting and to compare the delivered dose intensity, disease-free survival (DFS) and overall survival (OS) times, and toxicity between treatment arms in patients with breast cancer.

Methods.

Patients were randomized to receive preoperative FAC (5-FU, 500 mg/m²; doxorubicin, 50 mg/m²; cyclophosphamide, 500 mg/m²) every 21 days for four cycles or dose-intense FAC (5-FU, 600 mg/m²; doxorubicin, 60 mg/m²; cyclophosphamide, 1,000 mg/m²) plus G-CSF every 18 days for four cycles.

Results.

Two hundred two patients were randomly assigned. The median follow-up was 7.5 years. Patients randomized to FAC plus G-CSF had a higher pCR rate as well as clinical complete response rate; however, these differences were not statistically different from those with the FAC arm. Patients in the FAC + G-CSF arm had a higher delivered dose intensity of doxorubicin in the neoadjuvant and adjuvant settings than those in the standard FAC arm. DFS and OS times were not significantly different between the two groups. However, the OS and DFS rates were significantly higher for patients who achieved a pCR than for those who did not. Thrombocytopenia, febrile neutropenia, and infection rates were higher in the FAC + G-CSF arm.

Conclusions.

A higher delivered dose intensity of doxorubicin with the FAC + G-CSF regimen did not result in a statistically significant higher pCR rate. However, patients who achieved a pCR experienced longer DFS and OS times.     

Randomized comparison of etoposide-cisplatin vs. etoposide-carboplatin and irradiation in small-cell lung cancer: A Hellenic Co-operative Oncology Group study

PURPOSE:: To compare the efficacy and toxicity of etoposide and cisplatin(EP) with etoposide and carboplatin (EC) in combination withirradiation in small-cell lung cancer (SCLC). METHODS:: Previously untreated patients (pts) with SCLC and measurableor evaluable disease were randomized to receive either cisplatin50 mg/m² on days 1–2 or carboplatin 300 mg/m² on day 1,both combined with etoposide 300 mg/m² on days 1–3 every21 days for 6 treatment cycles. The vast majority of respondinglimited disease (LD) pts and complete responders (CR) with extensivedisease (ED), also received thoracic irradiation (TI) and prophylacticcranial irradiation (PCI) concurrently with the third cycle. RESULTS:: Of the 147 patients registered, 143 were eligible; median performancestatus (PS, WHO) was 1, and tumour stage was LD in 41 pts ofeach treatment group. The mean delay between cycles was 8 daysin the EP group and 9 in the EC group increasing in both armswith the number of treatment courses. The drug dose administeredper unit time as a proportion of the protocol dose was 74% and80% for the two groups respectively. Leukopenia, neutropenicinfections, nausea, vomiting, neurotoxicity and hyperergic reactionswere more frequent and/or severe in the EP group. The CR rateswere 57% and 58% for EP and EC respectively. Median survivalfor all pts was 12.5 and 11.8 months, respectively. CONCLUSION:: Both treatments proved to be effective, with no differencesin response and survival between the two treatment arms. TheEC regimen was associated with significantly less toxicity. small-cell lung cancer (SCLC), cisplatin, etoposide, carboplatin     

Dose-dependent impairment of testicular function in patients treated with cisplatin-based chemotherapy for germ cell cancer

BACKGROUND:: The enormous differences in semen quality following cisplatin-basedcombination chemotherapy reported in previous studies may becaused by differences in the cisplatin dosages. PATIENTS AND METHODS:: We examined thirty-three patients treated with conventional-dosePEB (cisplatin 20 mg/m² x 5, q3w, etoposide 100 mg/m² x 5 q3wand bleomycin 15 mg/m² q1w) and 21 patients treated with high-dosePEB (cisplatin 40 mg/m² x 5 q3w, etoposide 200 mg/m² x 5 q3wand bleomycin 15 mg/m² qlw). RESULTS:: The sperm density was significantly higher (median 5.83 mill/ml)in the conventionally-treated group than in the group of high-dose-treatedpatients (median 0.005 mill/ml) (p = 0.008). Azoospermia waspresent in 19% of the conventionally- and in 47% of the high-dose-treatedpatients. All patients treated with a cumulative cisplatin doseabove 600 mg/m² had severe oligospermia or azoospermia. Serumvalues of basal follicle-stimulating hormone (FSH) (median 27.2iu/l vs. 15.2 iu/l) and stimulated FSH (median 57.7 iu/l vs.28.4 iu/l) were significantly higher in the high-dose groupthan in the conventionally-treated group. No differences couldbe detected in basal or stimulated testosterone or in luteinizinghormone in serum. CONCLUSION:: In patients treated with PEB for testicular cancer, we foundstrong evidence that the impairment of spermatogenesis is dose-dependent. cytotoxic agents, fertility, spermatogenesis, Leydig cell function, testicular cancer     

A phase I investigation of the sequential use of methotrexate and paclitaxel with and without G-CSF for the treatment of solid tumors

BACKGROUND: Paclitaxel is a novel agent with significant activity in severalsolid tumors. Preclinical data suggested that methotrexate priorto pacitaxel would be synergistic. To determine the qualitativeand quantitative toxicity of this regimen we performed a phaseI study in patients with solid tumors. PATIENTS AND METHODS: Patients with solid tumors previously treated with no more thantwo prior chemotherapy regimens were given methotrexate intravenouslyon day 1, followed by pacitaxel, as a 24-hour infusion on day2. The starting dose (level ‘0’) was 40 mg/m formethotrexate and 135 mg/m for paditaxel. RESULTS: After achieving a maximum tolerated dose, additional patientswere enrolled with the addition of G-CSF 5 µg/kg/d ondays 4–13. At the starting dose level, dose-limit ingtoxicity consisting of neutropenic fever occurred in 3 of 4patients. At dose level–1, methotrexate 30 mg/m² and paclitaxel110 mg/m² neutropenic fever occurred in 7 of 10 patients duringthe first course. At dose level–2, methotrexate 23 mg/m²and paclitaxel 85 mg/m² neutropenic fever occurred in 1 of 7patients. To abrogate the neutropenia we explored the same combinationwith the addition of G-CSF. Neutropenic fever remained the onlydose-limiting toxicity. At dose level ‘0’ with G-CSF,1 of 7 patients developed doselimiting toxicity. At dose level1 plus G—CSF, methotrexate 40 mg/m² and pacitaxel 170mg/m² dose-limiting neutropenic fever occurred in 4 of 6 patients.Partial responses occurred in 4 of 41 patients entered on thisstudy. Pharmacokinetic data suggested that methotrexate didnot increase pacitaxel levels. CONCLUSION: The combination of methotrexate and paci taxel is feasible,but neutropenic fever, even with the addition of G—CSFprevents further escalations of paclitaxel beyond 135 mg/m²following methotrexate. phase I, methotrexate, paclitaxel, solid tumors     

GM-CSF,carboplatin, doxorubicin: a phase I study

Dose intensification has the potential to increase the response frequency of chemosensitive tumors to chemotherapy. G-CSF and GM-CSF offer the possibility of dose-intensifying chemotherapy without prohibitive myelosuppression. A phase I study was undertaken to identify the maximum tolerated dose (MTD) of carboplatin that could be administered with a fixed dose of doxorubicin, 60 mg/m², administered every 28 days. Further escalation of the carboplatin dose was then attempted, with the concomitant addition of GM-CSF 10 mg/kg per day on days 1–21. We had 21 patients, 13 with prior therapy, who were eligible. In all, 60 courses of therapy were delivered, all with doxorubicin and with carboplatin doses of 250 mg/m², 325 mg/m² and 400 mg/m². At carboplatin 400 mg/m² and doxorubicin 60 mg/m², thrombocytopenia was dose limiting. The addition of GM-CSF did not allow further escalation. Of the 6 patients treated with carboplatin 400 mg/m², doxorubicin 60 mg/m², and GM-CSF, grade 4 granulocytopenia and thrombocytopenia were seen in 4 and 5 patients, respectively. The severity of thrombocytopenia was related to the calculated carboplatin AUC and also to baseline platelet count and prior therapy. In addition, the interaction of GM-CSF and chemotherapy, especially carboplatin-based, may be more complex than originally anticipated.This investigation was supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA-14028, CA-28862, CA-12213, CA-13612, CA-32102     

Phase I/II study of intraperitoneal mitoxantrone in refractory ovarian cancer

BACKGROUND:: Mitoxantrone has demonstrable clinical activity when administeredintravenously in a wide range of malignancies. The feasibilityand toxicity of intra-peritoneal administration was establishedin a phase I study. The optimal dose from the phase I was subsequentlyevaluated in a phase II study. PATIENTS AND METHODS:: 19 patients with refractory malignancies and extensive abdominaldisease (13 ovarian cancer, 4 breast cancer, 2 mesothelioma)were entered in a phase I study. The dose of intraperitonealmitoxantrone was escalated from 10 mg/m², administered in 21of fluid via a Tenkhoff catheter, to 55 mg/m², in incrementsof 5 mg/m². Cycles were repeated every three weeks. Sixty-sevencycles of mitoxantrone were administered, the maximum tolerabledose being 25 mg/m². A phase II study at this dose was conductedin 14 patients with refractory ovarian cancer, all of whom hadpreviously received systemic platinum based therapy. Five ofthe 14 had also previously been treated with intraperitonealcarboplatin. Fifty-one cycles were administered. RESULTS:: The dose limiting toxicity in the phase I study was peritonealirritation and pain. Leucopenia was frequent at doses equalor greater than 30 mg/m². Three complete remissions were documentedin the phase I study (2 breast cancer and 1 ovarian cancer).There was no significant haematological toxicity in the phaseII assessment, though local toxicity precluded further therapyin 2 patients. No objective responses were seen in the phaseII evaluation. CONCLUSIONS:: These studies demonstrate the feasibility of intra-peritonealmitoxantrone therapy in patients with peritoneal disease, butdo not support its routine use in ovarian cancer. ovarian cancer, mitoxantrone, intraperitoneal therapy, phase I, phase II